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Review
Prehospital haemostatic dressings for trauma: a systematic review
  1. Adam J Boulton1,
  2. Christopher T Lewis2,
  3. David N Naumann3,
  4. Mark J Midwinter4
  1. 1University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
  2. 2NHS Highland, Raigmore Hospital, Inverness, Highland, UK
  3. 3NIHR Surgical Reconstruction and Microbiology Research Centre, Queen Elizabeth Hospital, Birmingham, UK
  4. 4Faculty of Medicine, School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia
  1. Correspondence to Dr Adam J Boulton, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK; adam.boulton{at}nhs.net

Abstract

Background Haemorrhage is a major cause of mortality and morbidity following both military and civilian trauma. Haemostatic dressings may offer effective haemorrhage control as part of prehospital treatment.

Aim To conduct a systematic review of the clinical literature to assess the prehospital use of haemostatic dressings in controlling traumatic haemorrhage, and determine whether any haemostatic dressings are clinically superior.

Methods MEDLINE and EMBASE databases were searched using predetermined criteria. The reference lists of all returned review articles were screened for eligible studies. Two authors independently undertook the search, performed data extraction, and risk of bias and Grading of Recommendations, Assessment, Development and Evaluation quality assessments. Meta-analysis could not be undertaken due to study and clinical heterogeneity.

Results Our search yielded 470 studies, of which 17 met eligibility criteria, and included 809 patients (469 military and 340 civilian). There were 15 observational studies, 1 case report and 1 randomised controlled trial. Indications for prehospital haemostatic dressing use, wound location, mechanism of injury, and source of bleeding were variable. Seven different haemostatic dressings were reported with QuikClot Combat Gauze being the most frequently applied (420 applications). Cessation of bleeding ranged from 67% to 100%, with a median of 90.5%. Adverse events were only reported with QuikClot granules, resulting in burns. No adverse events were reported with QuikClot Combat Gauze use in three studies. Seven of the 17 studies did not report safety data. All studies were at risk of bias and assessed of ‘very low’ to ‘moderate’ quality.

Conclusions Haemostatic dressings offer effective prehospital treatment for traumatic haemorrhage. QuikClot Combat Gauze may be justified as the optimal agent due to the volume of clinical data and its safety profile, but there is a lack of high-quality clinical evidence, and randomised controlled trials are warranted.

Level of evidence Systematic review, level IV.

  • Prehospital
  • trauma
  • haemorrhage
  • haemostatic

https://doi.org/10.1136/emermed-2018-207523

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    Introduction

    Uncontrolled haemorrhage remains a major cause of mortality and morbidity both in military and civilian trauma.1 A large proportion of mortality occurs prior to patients reaching hospital, and so effective treatments delivered in the prehospital setting are potentially life-saving.1 2 Although the tourniquet has been a life-saving intervention in prehospital care—particularly in the military setting3—they cannot be applied to junctional zones (groin, axilla and neck), and are unsuitable for wounds of the head and trunk. Using gauze dressings to compress these wounds has traditionally been the mainstay of immediate treatment.4 These junctional zones represent a challenge as maintaining effective compression of these areas is technically difficult and they contain large vascular structures which cannot be controlled proximally with simple prehospital interventions.2 5 Tourniquets applied to extremities are not without risk and can themselves be a cause of significant morbidity.6 Additional therapeutic adjuncts may therefore be considered.

    Haemostatic dressings contain agents to enhance blood clotting and offer additional haemorrhage control to standard gauze. They can be relatively simple to apply and are familiar to prehospital providers due to the traditional use of standard gauze dressings and compression to control haemorrhage.7 Pusateri et al named seven criteria for the ideal prehospital haemostatic dressing as: the ability to stop large vessel arterial and venous bleeding within 2 min of application; ready to use without on-scene mixing or preparation; simple to apply by those with minimal training including the casualty; lightweight and durable; a minimum 2-year shelf-life and be stable at extremes of temperature; be safe to use; and be relatively inexpensive.7 Haemostatic agents are licensed for external use but not for intracavity use.5 Haemostatic agents were initially developed and evaluated using a variety of animal models. This made comparison of agents challenging, and so a standardised swine femoral artery injury has been developed that is now widely used.8 The haemostatic agents are grouped into three types based on their mechanism of action: (A) factor concentrators; (B) mucoadhesive agents; and (C) procoagulant supplements.5

    1. Factor concentrators: Factor concentrators were the first generation of haemostatic agents and the mostly widely used is QuikClot granules.9 10 The original QuikClot was a granular preparation of zeolite which acted by rapidly absorbing water and thus concentrating the platelets and coagulation factors to encourage clotting.4 5 A newer generation called QuikClot ACS used zeolite beads in mesh bag and was adopted by the US and UK military from 2003 and 2004, respectively.5 The zeolite caused an exothermic reaction and resulted in burns for a number of patients and was subsequently withdrawn from the market.5 TraumaDex is a powder preparation of a plant-derived starch which also acts to rapidly absorb water and concentrate the blood, however it does not result in an exothermic reaction.5

    2. Mucoadhesive agents: Mucoadhesive agents act by strongly adhering to the tissues and creating a seal around the bleeding site.5 Most use chitosan impregnated gauze and include HemCon, ChitoFlex, ChitoGauze and Celox.4 All have been employed at some stage by the US and UK military.5 11 Another mucoadhesive agent dressing is the Modified Rapid Deployment Hemostat (mRDH) which also has procoagulant supplementary activity.12

    3. Procoagulant supplements: The procoagulant supplements act by providing a high local concentration of coagulation factors and therefore directly activate the coagulation cascade.5 The most widely used is QuikClot Combat Gauze which has recently been reported in use by the US military.13

    Systematic reviews of prehospital haemostatic agents have been undertaken in 20115 and 2013,4 but were limited by a paucity of clinical evidence, instead concentrating on preclinical, experimental studies. In a rapidly evolving field, it is timely to undertake another systematic search of the published literature in order to determine what clinical evidence is available for the prehospital utilisation of haemostatic agents in modern practice.

    The current systematic review aims to assess the civilian and military prehospital use of haemostatic dressings to control haemorrhage following trauma, and determine whether one haemostatic dressing is superior in terms of clinical outcomes when compared with the remainder.

    PICO statement (population, intervention, comparison, outcome)

    The population of interest are patients with traumatic haemorrhage. The intervention is the use of prehospital haemostatic dressings. Comparisons will be made by the type of haemostatic dressing used, military or civilian application, medical providers, patient characteristics, mechanism of injury (MOI), wound details and any physiological parameters. The outcomes to be assessed are cessation of bleeding, rates of rebleeding, mortality and adverse events or safety concerns.

    Methods

    A systematic review was undertaken in order to examine the utilisation of haemostatic dressings within the prehospital environment for patients with trauma. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines have been followed in the conduct and reporting of this systematic review.14 This systematic review was prospectively registered on PROSPERO (Reference: CRD42017080129).

    Research questions

    The following research questions were used to form the basis of this systematic review:

    1. What haemostatic dressings have been used within the prehospital environment for patients with trauma?

    2. What is the reported clinical efficacy of haemostatic dressing in controlling traumatic haemorrhage in the prehospital setting?

    3. Which haemostatic dressing has superior clinical outcomes when compared with others?

    Eligibility criteria

    Original articles reporting the use of any haemostatic dressings for traumatic haemorrhage in both military and civilian prehospital settings were included. Patients of all ages were eligible for inclusion. Preclinical (animal model and in vitro) studies were excluded, but all clinical studies were eligible for inclusion, regardless of methodological design. This review investigated haemostatic dressings and bandages, therefore haemostatic sponges, foams or devices were not eligible for inclusion. Clinical use of haemostatic dressings after the prehospital period (such as those used in the ED or operating theatre) was not included.

    Search strategy

    OVID SP was used to search the MEDLINE and EMBASE databases. MEDLINE from 1946, MEDLINE In-Process & Other Non-Indexed Citations and EMBASE from 1974 were used. Reference lists of returned reviews and eligible studies were also searched. An OVID SP multiple purpose search was performed for all search terms. An example of a search is shown in online supplementary file 1. The search terms were as follows: ‘prehospital’, ‘pre-hospital’, ‘out-of-hospital’, ‘civilian’, ‘military’, ‘trauma’, ‘haemorrhage’, ‘haemorrhage’, ‘wounds’, ‘haemostatic’, ‘hemostatic’, ‘quikclot’, ‘hemcon’, ‘celox’, ‘chitogauze’, ‘chitoflex’, ‘chitosan’ and ‘mrdh’. All duplicate studies were removed.

    Supplementary file 1

    Study selection

    Two authors (AJB and CTL) independently reviewed all returned studies for inclusion. Titles and abstracts of all returned articles were screened for eligibility and full texts were obtained for all articles of interest. The reference lists of included studies and relevant reviews were screened in the same manner.

    Data extraction

    Data were extracted independently by two authors (AJB and CTL) using predetermined criteria. Study-level data included year of publication and first author, country of origin, military or civilian, patient eligibility criteria, individual study design and type of haemostatic dressings. Patient-level data included patient demographics (age and gender), injury severity, MOI and wound details. The outcome measures extracted were mortality, cessation of bleeding, rebleeding rates and adverse events or safety concerns.

    Assessment of risk of bias and quality of evidence

    Randomised controlled trials (RCT) were assessed for risk of bias using the Cochrane Collaboration risk of bias tool.15 The Newcastle-Ottawa scale was used to assess the risk of bias for non-randomised (observational cohort and case–control) studies.16 The quality of the evidence of included studies was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology.17 These assessments were independently performed by two authors (AJB and CTL).

    Results

    Search results

    Up to 712 articles were identified using our search criteria, and after duplicates were removed, 470 articles remained. The titles and abstracts were screened, and this yielded 60 articles that were potentially eligible, and for which full texts were reviewed. Nine original articles were excluded for the reasons stated in figure 1.12 18–25 After review of full texts, 13 original articles met all eligibility criteria for inclusion. An additional four original eligible studies were identified from the reference lists of non-included articles. Therefore, 17 original studies met all inclusion criteria, and are summarised in this review (figure 1).9–11 13 26–38

    Figure 1
    Figure 1

    Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.

    Study characteristics

    The study characteristics are summarised in table 1. There were eight civilian26–28 31 35–38 and eight military studies10 11 13 29 30 32–34 and one including both civilian and military populations.9 These include seven studies from the US military in Iraq and/or Afghanistan,9–11 13 29 30 32 four from the USA,9 26 31 38 two from Israel,33 34 two from the Netherlands,27 35 and one from each of France and Iran.28 37 The majority of these studies (n=15) were observational studies, with only one being randomised.28 Four of the observational studies were conducted prospectively,27 30 33 37while the remainder were retrospective. There was one case report.36 The number of centres included varied with seven studies including one centre,10 28 32 34–37 and four studies being multicentred.27 30 31 38 The remainder (n=6) did not report the number of centres.9 11 13 26 29 33

    View this table:
    Table 1

    Study characteristics

    Those studies reporting an indication for haemostatic agent use typically included failure of conventional methods to control haemorrhage.26 27 31 32 34–37 For one study, the indication was not related to failure of conventional methods and instead concerned stab injuries with a wound length greater than 3 cm where bleeding was a clinical concern.28 Nearly half of the studies (n=8) did not report an indication for haemostatic use.9–11 13 29 30 33 38

    The majority of studies (n=11) did not report a source of funding. Two studies had a declared relationship with the haemostatic manufacturer,26 32 while the others were funded by the local military,10 34 or identified that no funding was required.27 31

    Patient characteristics

    Patient characteristics for all studies are summarised in online supplementary file 2. There were 809 patients, including 469 military and 340 civilian, with 885 haemostatic applications. Of the studies reporting demographics, there were 366/446 (82%) male patients, and the average age ranged from 22 to 59 years. One study presented an injury severity score.31 Three studies presented physiological parameters,13 28 34 with two studies comparing these between the haemostatic group and the comparator.13 28 Except for respiratory rate in one study,13 these parameters did not significantly differ within these studies.13 28

    Fifteen studies reported the site of the injury with the majority being an extremity (n=447).9–11 13 26–28 31–38 One study indicated haemostatic use solely for extremity wounds, whereas others included all wounds.28 There was considerable heterogeneity in injury patterns between studies. Military studies had a higher rate of penetrating trauma in comparison to civilian studies (79% vs 64%). There were 59 applications to junctional areas (pelvis, shoulder, axilla, buttocks, groin and neck).2 34 36 Four studies reported the source of bleeding as arterial, venous or mixed.11 26 27 37

    Types of haemostatic dressings

    The haemostatic dressings reported in studies are summarised in figure 2. There were six different types of haemostatic dressings reported, including Celox (21 applications),32 Celox gauze (83 applications),28 35 ChitoGauze (66 applications),27 HemCon (139 applications),10 11 26 29 QuikClot granules (131 applications),9 10 QuikClot ACS+ (23 applications)36 and QuikClot Combat Gauze (420 applications).13 31 33 34 37 38 QuikClot Combat Gauze was the most commonly reported, with 420 applications in six studies.13 31 33 34 37 38 In the most recent studies, QuikClot Combat Gauze was used more often compared with prior studies. Of the seven studies published since 2015,13 27 28 31 34 37 38 five used QuikClot Combat Gauze,13 31 34 37 38 whereas only one study prior to 2015 used QuikClot Combat Gauze.33

    Figure 2
    Figure 2

    Haemostatic agent use by year and setting. References are indicated in parentheses. C, civilian; M, military.

    Clinical efficacy

    The outcome measures are summarised in table 2. Fifteen studies reported a cessation of bleeding rate.9–11 13 26–28 31–38 The cessation of bleeding success ranged from 67% to 100% with a median reported rate of 90.5%. Pooling the cessation rates to compare types of haemostatics was not justified due to high clinical and methodological heterogeneity of the studies. As summarised in table 1 and online supplementary file 2, there was a large variability in study participants, MOI, injury location and the indications for haemostatic use. Only one study reported the proportion of applications that rebled.27 This was using ChitoGauze and was 2 of 66 (3%).27 One study reported successful simultaneous placement of haemostatic dressing and tourniquet.38 There were two reported instances in which a tourniquet was placed and later, a haemostatic dressing was applied to augment control of venous bleeding.38 No other studies reported data related to haemostatic use in conjunction with tourniquet placement.

    View this table:
    Table 2

    Outcome measures

    Haemostatic failure

    Six studies reported potential reasons for failure of the haemostatic.9 11 26 27 33 35 We were able to categorise these as due to user error or wound characteristics (table 2). Of the 28 reasons reported, 19 were due to wound characteristics and nine due to user error. User error factors included: applying the wrong side of a HemCon bandage,26 incomplete wound coverage26 and not applying the haemostatic deep to the source of bleeding, for example, in a penetrating groin wound.26 27 Wound factors typically related to the inability to apply the haemostatic to the source of bleeding, for example, large cavitational wounds or pelvic injuries.9 11 33

    Adverse events

    Eight studies reported no adverse events or safety concerns.27 28 31–33 35–37 Two studies reported adverse events with the use of QuikClot granules, all related to burns.9 10 There were five reported instances of burns in 105 applications of QuikClot granules (4.8%). These events did not appear to be related to any specific application technique. There were no adverse events reported with use of QuikClot Combat Gauze,31 33 37 HemCon,10 Celox Gauze,28 35 Celox granules,32 ChitoGauze27 and QuikClot ACS+.36 The remaining seven studies did not report information regarding adverse events.11 13 26 29 30 34 38

    Risk of bias assessment

    There was a large variability in the risk of bias according to the Newcastle-Ottawa Scale (n=15) and Cochrane Collaboration risk of bias tool (n=1) as shown in online supplementary file 3 and online supplementary file 4, respectively. Nine of the studies did not measure the outcome of cessation of haemorrhage in a robust manner or it was not clear in the manuscript and therefore did not score on this domain.9 11 26 29–31 33 35 37 Furthermore, some studies presented a broad data set with haemostatic data as a subgroup.29 30 Many variables for this haemostatic subgroup were not explicitly reported, therefore assessment of representativeness, demographic factors and comparability was not possible.

    Quality of evidence

    The quality of evidence according to the GRADE system for included studies is shown in online supplementary file 5. Most (n=16) were rated as ‘low’ or ‘very low’, principally due to their observational nature.9–11 13 26 27 29–38 Five studies were downgraded to ‘very low’ due to a high risk of bias in accordance with the GRADE assessment.9 11 30 36 37 The RCT was downgraded to ‘moderate’ due to methodological risk of bias inherent to an open-label trial.28

    Discussion

    In this systematic review of the clinical literature regarding prehospital application of haemostatic dressings, we have found 17 studies of varying methodology that report successful control of traumatic haemorrhage in the majority of applications. These included over 800 civilian and military patients in a range of countries. Of the studies that reported an indication for haemostatic use, the most common reason was the failure of conventional methods, indicating the potential for haemostatic dressings to offer a therapeutic adjunct to conventional haemorrhage control measures. A range of prehospital haemostatics have been used, with the most common in recent years being QuikClot Combat Gauze (47% of all applications). It is unclear from the current literature if one of these confers a clinically superior effect. Adverse events have only been reported with QuikClot granules (burns), but not all studies reported adverse events. In studies documenting adverse events, nil were reported with the use of QuikClot Combat Gauze, HemCon, Celox Gauze, Celox granules, ChitoGauze and QuikClot ACS+.

    The US military has favoured QuikClot Combat Gauze since 2008,39 and the Israel Defence Forces have nominated it as their agent of choice.34 In the UK military, Celox-coated gauze has been favoured since the update to the Clinical Guidelines for Operations in 2013.40 The US military added Celox gauze and ChitoGauze to their recommended agents in 2014, when the Tactical Combat Casualty Care guidelines were updated based on preclinical and civilian evidence.41 Although our review highlights the lack of high-quality evidence for haemostatics, and the absence of direct clinical comparative studies, these agents have all shown good cessation of bleeding in more than one study each, justifying these choices.

    Previous systematic reviews have concluded that haemostatic dressings provide a potentially effective therapeutic adjunct to conventional haemorrhage control measures, and have demonstrated a paucity of clinical evidence to determine if one haemostatic dressing is clinically superior.4 5 42 43 These reviews included between three and seven clinical studies. Ours is the largest systematic review of prehospital use of haemostatic dressings to date, and includes assessments of the risk of bias and quality of evidence of included studies. Based on our review of 17 studies we are able to suggest more confidently that haemostatic dressings represent an effective traumatic haemorrhage control measure. In keeping with previous reviews, we were not able to conclude whether one haemostatic dressing has superior clinical outcomes, since there have been no randomised comparisons between agents in the clinical literature.

    Since QuikClot Combat Gauze is the most widely studied haemostatic dressing in the prehospital environment, and has demonstrated a good safety profile, we recommend that it remain the haemostatic dressing of choice for patients in this setting. However, this recommendation is limited by the under-reporting of efficacy of other haemostatics in a clinical context, and the dependence on non-human (preclinical and animal studies) evidence for the justification of other agents. ChitoGauze and Celox gauze have also shown promise in recent studies, and although there are fewer studies of these agents, their continued use is warranted based on evidence published so far.

    Haemostatic agents have been particularly desirable in the remote damage control setting, where early cessation of haemorrhage is paramount in the survival of casualties before they arrive in hospital.1 From the variation in types of agents, settings and injury patterns, it may be postulated that this field is still in its early phase of discovery, adoption and evidence gathering. In the presence of heterogeneity in practice, and sparsity of data that might place one agent as superior, it is likely that there is considerable equipoise, and more RCTs are justified in order to reduce this uncertainty. Trials within the remote damage control resuscitation setting have considerable logistic, financial and ethical implication, which may explain why only one RCT was discovered in our review of the literature. Other prehospital trials including patients with trauma are under way,44 which makes a case for a randomised study of haemostatic agents both plausible and justified.

    It is notable that although haemostatic agents have been recommended for use in areas where tourniquets cannot be used (such as junctional zones and the trunk),2 we found that there were a large number of applications to the extremities. This is likely due to the predominance of extremity trauma in recent conflicts,1 and the presence of coagulopathy that might hinder the cessation of bleeding. It appears that haemostatic agents have been used in two broad contexts: the cessation of bleeding that could not be controlled by tourniquets due to anatomical location (such as the groin or axilla); but also for bleeding that could not be controlled distal to an applied tourniquet. This may be an indication that the full scope for these agents is being discovered in real time by the resourcefulness of prehospital emergency medical personnel.

    Direction of research

    The findings in this review may direct future research questions. For example, there is currently no consensus on which agent may be superior, and in which circumstances and anatomical locations. Furthermore, it is unknown whether prehospital personnel should use a single agent or have access to multiple types of dressings, applying them according to mechanism and location of injuries. Future prospective studies may enable more consistent practice, with the development of treatment protocols for the optimal utilisation of these haemostatic agents. Although not included within this review, there is also uncertainty regarding the use of haemostatic sponges, foams and injectables, and whether there are indications for their combination with the haemostatic dressings described here.2

    Limitations

    This systematic review is principally limited by the quality of the studies included, as highlighted in the risk of bias and GRADE quality assessments. The included study populations represent a heterogeneous sample with different indications for haemostatic use, and the prehospital providers also vary. Likewise, reporting of outcome measures was variable with some studies presenting haemostatic dressing data as part of broad data set, therefore preventing extraction of haemostatic dressing specific outcomes.

    Conclusion

    Haemostatic dressings appear to offer an effective traumatic haemorrhage control measure. QuikClot Combat Gauze has the greatest volume of evidence of safety and efficacy. In addition, Celox-coated gauze, ChitoGauze and HemCon have shown promising data. There is a sparsity of high-quality, prospective evidence to precisely define the optimal use of haemostatic dressings in prehospital trauma management, and lack of consensus over the most effective products. Despite logistical challenges, there is both justification and precedent for RCTs to compare these agents, in order to optimise clinical guidelines on their use in the prehospital setting.

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    Footnotes

    • Contributors Study design: AJB, CTL, DNN, MJM. Study conduct: AJB, CTL, DNN. Drafting of manuscript: AJB, CTL, DNN. Review of manuscript: AJB, CTL, DNN, MJM.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Patient consent Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.